Biocompatable nanoscale drug carriers incorporating targeting information have the potential to provide substantial improvement of drug delivery methods with high efficacy and minimal toxicity. Nanostructures can combine polyvalent display of small molecules (Hrkach, J., et al. Science Translational Medicine, Vol. 4 128ra139-128ra139 (2012); herein incorporated by reference in its entirety), aptamers (Farokhzad, O. C., et al. Cancer Research, Vol. 64 7668-7672 (AACR, 2004); herein incorporated by reference in its entirety), antibodies (Qian, X., et al. Nat Biotechnol, Vol. 26 83-90 (2007); herein incorporated by reference in its entirety), and proteins (Davis, M. E., et al. Nature, Vol. 464 1067-1070 (2010); Choi et al. Proceedings of the National Academy of Sciences, Vol. 107 1235-1240 (2010); herein incorporated by reference in their entireties) on their surfaces designed to release drugs at a targeted site (Vance et al. Advanced Drug Delivery Reviews, Vol. 61 931-939 (2009); herein incorporated by reference in its entirety). Most work in this area has focused on cancer therapies, with very few examples targeting cardiovascular pathologies (Chan, J. M., et al. Proceedings of the National Academy of Sciences, Vol. 107 2213-2218 (2010); herein incorporated by reference in its entirety). Specifically, cardiovascular interventions, such as bypass grafting, or angioplasty with and without stenting have limited durability due to eventual arterial reocclusion. This reocclusive process initiated at the site of intervention involves inflammatory processes, as well as cellular proliferation and migration, among other events (Kornowski, R., et al. Journal of the American College of Cardiology, Vol. 31 224-230 (1998); herein incorporated by reference in its entirety). Ultimately, this arterial injury response leads to what is known as neointimal hyperplasia, which narrows the lumen of the blood vessel. Developing a therapy to effectively prevent the formation of neointimal hyperplasia, while simultaneously promoting vascular healing, is a significant unmet clinical need.
The physiological gas nitric oxide (NO) has many vascular protective properties (Barbato, J. E. & Tzeng, E. Journal of Vascular Surgery, Vol. 40 187-193 (2004); Garg, U. C. & Hassid, A. J. Clin. Invest., Vol. 83 1774 (1989); Kubes et al. Proceedings of the National Academy of Sciences, Vol. 88 4651-4655 (1991); Dubey et al. J. Clin. Invest., Vol. 96 141 (1995); herein incorporated by reference in their entireties), including inhibition of the processes that lead to neointimal hyperplasia (Alef et al. Nitric Oxide, Vol. 26 285-294 (Elsevier Inc., 2012); herein incorporated by reference in its entirety). Furthermore, NO is known to promote the healing of the inner layer of the arterial wall populated by endothelial cells (Ziche, M., et al. J. Clin. Invest., Vol. 94 2036 (1994); herein incorporated by reference in its entirety). Systemic delivery of NO donors has limited clinical application due to toxicity and potential side effects (Keefer, L. K. Annual review of pharmacology and toxicology, Vol. 43 585-607 (2003); herein incorporated by reference in its entirety). Local delivery of NO has shown efficacy in vivo (Kapadia, M. R., et al. Journal of Vascular Surgery, Vol. 47 173-182 (2008); Fleser, P. S., et al. Journal of Vascular Surgery, Vol. 40 803-811 (2004); Selcuk, H., et al. Cardiovasc Intervent Radiol, Vol. 28 242-245 (2005); herein incorporated by reference in its entirety), but is not clinically translatable because it requires invasive procedures for delivery or is limited to single dose application. NO is a challenging molecule to deliver owing to its short half-life, rapid metabolism, and reactivity (Rassaf, T., et al. J. Clin. Invest., Vol. 109 1241-1248 (2002); herein incorporated by reference in its entirety). Systemically delivered NO-based approaches have been limited in their clinical translation due to non-clinically tenable delivery schemes (e.g., extended exposure to NO gas), systemic side effects (e.g., bleeding and hypotension from the large doses of NO delivered from NO donors to achieve efficacy), or safety concerns (e.g, gene therapy).
Peptide amphiphiles (Hartgerink et al. P Natl Acad Sci USA 99, 5133 (2002); Hartgerink et al. Science 294, 1684 (2001); herein incorporated by reference in their entireties) (PAs) are a class of self-assembling molecules that are composed of a hydrophobic segment conjugated to a sequence of amino acids. PAs can form long, high aspect ratio cylindrical filaments in water and have been studied for a range of applications in regenerative medicine (Mata et al., Biomaterials 31, 6004 (2010); Shah et al., P Natl Acad Sci USA 107, 3293 (2010); Huang et al. Biomaterials 31, 9202 (2010); Webber et al., P Natl Acad Sci USA 108, 13438 (2011); herein incorporated by reference in their entireties). PA bioactivity is derived from presentation of peptide sequences on the surface of self-assembled nanostructures that form in solution. The rheological properties of these materials can be tuned by concentration and peptide sequence (Pashuck et al. Journal of the American Chemical Society 132, 6041 (2010); herein incorporated by reference in its entirety).